Minimal change oesophagitis: a disease with characteristic differences to erosive oesophagitis.

BACKGROUND: The majority of gastro-oesophageal reflux disease (GERD) seems to be non-erosive reflux disease. Nonerosive reflux disease includes minimal change oesophagitis (whitish or reddish, oedematous change and erosion that is not regarded as mucosal break) and no endoscopic abnormalities. AIM: To investigate the accurate proportion of those with minimal change oesophagitis and to clarify its characteristics. In addition, we evaluated the effect of famotidine (40 mg/day) in those with minimal change. METHODS: Prospective endoscopic assessment was performed for consecutive 606 out-patients. Of the 582 patients suitable for analysis, 347 were non-treated. The latter were divided into those with erosive GERD or minimal change, and their endoscopic findings and characteristics were compared. RESULTS: Among 347 non-treated patients, 88 (25%) had erosive GERD and 249 (72%) had minimal change. Compared with patients who have erosive GERD and those with minimal change, the latter were less likely to have hiatal hernia or bile reflux, but more likely to have gastric atrophy. Symptomatic patients (n = 55) with minimal change oesophagitis were more likely to have hiatal hernia than those who were asymptomatic (n= 194). Most patients preferred taking famotidine on-demand, during a 4-week follow-up period. CONCLUSIONS: Most non-erosive reflux disease can be classified as minimal change oesophagitis, and that have different characteristics from erosive GERD. On-demand famotidine may be a suitable alternative treatment for patients with minimal change disease.

Interleukin-5 transgenic mice show augmented resistance to Angiostrongylus costaricensis infection.

To determine the possible role of eosinophils in Angiostrongylus costaricensis infection, both interleukin-5 (IL-5) transgenic (Tg) and non-transgenic (non-Tg) C3H/HeN mice were infected with A. costaricensis third-stage larvae. IL-5 Tg mice demonstrated greater resistance than non-Tg mice to A. costaricensis, as shown by lower adult worm recovery, smaller adults, fewer eggs in the intestinal wall and fewer larvae passed in the feces. Both mice showed similar antigen-specific IgA and IgGI antibody responses, although IgA was more prominent than IgG1. Egg deposition and inflammatory responses in the intestinal walls were milder in IL-5 Tg mice than in non-Tg mice. The eggs with developed larvae, deposited in the intestinal walls of IL-5 Tg mice, were surrounded by numerous degranulating eosinophils and sometimes with Splendore-Hoeppli deposits. The data suggest that eosinophils are involved in the resistance of the mouse during primary infection with A. costaricensis.

Elimination of lymphocytes, but not eosinophils, by Fas-mediated apoptosis in murine schistosomiasis.

Infection with the helminth parasite Schistosoma mansoni is associated with a pathogenic granulomatous response to parasite eggs. Multiple cell types constitute the granuloma with eosinophils achieving numerical dominance. We hypothesize that eosinophil dominance is achieved by selective apoptosis in lymphocytes. We report here that lymphocytes from both the spleens and granulomas of S. mansoni-infected mice undergo apoptosis. We also show that granuloma lymphocytes are more susceptible to Fas-FasL-mediated apoptosis than spleen lymphocytes and this apoptosis may be related to antigen concentration. Conversely, eosinophils from the granuloma and spleens of S. mansoni-infected mice are resistant to apoptosis in vivo and are protected in vitro from Fas-FasL-mediated apoptosis by the absence of FasL expression in the presence of Fas expression. Finally, the apoptotic regulatory molecules Bcl-2, Bcl-xL, and Bax, do not appear to play a significant role in the regulation of eosinophil apoptosis in the schistosome granuloma.

Identification of the prelinitis condition in gastric cancer and analysis of TGF-beta, TGF-beta RII and pS2 expression.

In the present study, we performed an immunohistochemical examination of the expression of transforming growth factor-beta (TGF-beta), TGF-beta type II receptor (TGF-beta RII) and a trefoil peptide, pS2, in the several types of gastric cancer. The TGF-beta:TGF-beta RII ratios of IIc-like type and Ménétrier type closely resembled that of linitis type. pS2 was intensely expressed in cytoplasm of the superficial and foveolar epithelium, as well as in scirrhous type gastric cancers which retained the gastric or intestinal phenotype. However, pS2 expression was significantly (p < 0.05) reduced in linitis type gastric cancers (1 of 6; 17%) when compared with other scirrhous types of gastric cancers (13 of 22; 59%). A decrease in the TGF-beta:TGF-beta RII ratios in linitis type, IIc-like type and Ménétrier type gastric cancers may be associated with the fibrosis seen in these types of cancer. Furthermore, reduction of pS2 expression in linitis type gastric cancer may represent a dedifferentiation of the cancer from gastric or intestinal phenotype. Judging by the expression patterns of TGF-beta, TGF-beta RII and pS2, it is possible that IIc-like type and Ménétrier type gastric cancers are precursor lesions of linitis type gastric cancer.

SCID mice show a similar susceptibility to Angiostrongylus cantonensis as do wild-type mice of the C.B-17 strain.

C.B-17-SCID/SCID (SCID) mice infected with Angiostrongylus cantonensis yielded a high percentage of worm recovery and did not show any body weight loss until day 24 postinfection. Unexpectedly, C.B-17-+/+(+/+) mice also produced a similar worm burden containing well-developed worms. This is probably attributable to the observation that +/+ mice failed to induce eosinophilia in cerebrospinal fluid (CSF) despite their production of antigen-specific IgA and IgGI; +/+ mice have defective bone-marrow eosinopoiesis, which in turn results in reduced blood and CSF eosinophilia. Interleukin 5 (IL-5) production in +/+ mice is similar to that in BALB/c and C57BL/6 mice. However, bone-marrow eosinopoiesis in response to IL-5 is markedly suppressed in +/+ mice. This is probably associated with impaired expression of common beta-chain mRNA in bone-marrow cells of +/+ mice, which leads to the failure of bone-marrow eosinopoiesis. Hence, +/+ mice may serve as a useful model for the elucidation of eosinophil production in the mouse and for determination of the relationship between parasite infection and the eosinophil.

[Prognostic factors of hepatocellular carcinoma: analysis by the proportional hazard model].

Five hundred fifty patients hospitalized to our hospital during 1990 to 1999 were studied. Subjects consisted of 413 males and 102 females and mean age was 62.1 years. Association with HBV infection, HCV infection and both infection was 11.1%, 78.4% and 2.5% respectively. According to the criteria based in Liver Cancer Study of Japan, 5 year survival rate in clinical stage I, II, III was 42.3%, 38.8% and 17.5%. Tumor morphology was nodular type in 78.9%, massive type in 9.1% and diffuse type in 10.5% of cases. Portal tumor thrombus and distal metastasis were observed in 19.9% and 6.3% of all cases. The 1-, 3- and 5-year survival rate in patients received any therapy was 80.8%, 44.6% and 28.7%, respectively. Analysis by the proportional hazard model showed that HBV infection, advanced clinical stage, multiple tumors, a tumor diameter in excess of 5 cm and AFP positivity were shown as significant factors on poor prognosis.

Immunolocalisation of PIVKA-II in paraffin-embedded specimens of hepatocellular carcinoma.

AIMS/BACKGROUND: Although serum PIVKA-II has been widely used as a tumor marker for hepatocellular carcinoma (HCC), little information is available concerning tissue PIVKA-II, and detection of tissue PIVKA-II in paraffin-embedded tissue specimens of HCC is also considered difficult. METHODS: Paraffin-embedded HCC tissues obtained at autopsy from 22 patients were subjected to immunohistochemical staining using the antibody MU-3 (Eisai Co., Ltd.) after microwave antigen retrieval. RESULTS: PIVKA-II was mainly detected in the cytoplasm of HCC cells. The intensity of tissue PIVKA-II staining was not correlated with serum PIVKA-II levels or with the histotogical differentiation of HCC. However PIVKA-II staining tended to be more intense in tissue from patients with portal tumor thrombus, distant metastases, or a longer duration of HCC. CONCLUSION: This method of immunohistochemical staining is easy and simple to use and may be helpful for detecting tissue PIVKA-II in paraffin-embedded HCC specimens.

Polaprezinc protects gastric mucosal cells from noxious agents through antioxidant properties in vitro.

BACKGROUND: Polaprezinc has been shown to exert an anti-oxidant property in a tube experiment, protect gastric mucosa from experimental ulcerations in vivo, and accelerate the healing of gastric ulcer in humans. AIM: To examine a possible protective effect of polaprezinc on oxidant-mediated injury in primary monolayer cultures of rat gastric fundic mucosa. METHODS: Cytotoxicity was quantified by measuring 51Cr release. Whether or not polaprezinc exerts an antioxidant property was investigated by determining the effect of this agent on hydrogen peroxide (H2O2)-induced injury. The effects of polaprezinc on superoxide (O2-. ) generation as well as on ethanol (EtOH)-induced injury were also examined. Generation of O2-. was assessed by the reduction in cytochrome c. RESULTS: H2O2 caused a time- and dose-dependent increase in 51Cr release. The dose-response curve of 51Cr release by H2O2 shifted to the right in the presence of polaprezinc. Polaprezinc, at submillimolar concentrations, prevented H2O2-induced 51Cr release. EtOH also caused a dose-dependent increase in 51Cr release, which was prevented by the addition of polaprezinc. The incubation of cells with EtOH caused an increase in cytochrome c reduction, as the concentrations of EtOH increased. Polaprezinc inhibited EtOH-induced cytochrome c reduction. Protection by polaprezinc was microscopically associated with the prevention of monolayer disruption. CONCLUSIONS: Polaprezinc is antioxidative and directly protects gastric mucosal cells from noxious agents through its antioxidant properties in vitro. This finding may provide the theoretical basis for the usage of an antiulcer drug with antioxidant properties for the treatment of gastric inflammation, such as that induced by ethanol.

Activated eosinophils are the major source of Th2-associated cytokines in the schistosome granuloma.

Eosinophils are a numerically dominant cell population within the schistosome granuloma. These granuloma eosinophils can produce a variety of cytokines, including IL-2, IL-4, IL-5, and IFN-gamma. Therefore, eosinophils may play a key role in the determination of the unique cytokine microenvironment within the granuloma milieu. These studies investigated the potential role of eosinophils in the regulation of granuloma immunopathology. We have characterized spleen- and granuloma-derived eosinophils based on cellular activation and cytokine production during the development of murine schistosomiasis. Based on the criteria of hypodensity and CD69 expression, granuloma eosinophils were highly activated and very homogeneous at 7 and 11 wk postinfection. Splenic eosinophils were also activated at 7 wk postinfection, but were much more heterogeneous than their granuloma counterparts. By 11 wk postinfection, few hypodense splenic eosinophils were observed. Eosinophils represented the majority of cytokine-producing cells in the granuloma and were a dominant source of IL-4. Eosinophils also produced IL-2, IL-5, and IFN-gamma, using the criteria of mRNA in situ hybridization and intracellular cytokine staining by FACS. Granuloma eosinophil activation and cytokine production were greatest at the time of maximum granuloma formation, i.e., 10-12 wk after initial cercarial exposure. Therefore, locally activated eosinophils, not Th2 lymphocytes, produce the majority of Th2 cytokines in the granuloma milieu and may be important determinators of immunopathology in schistosomiasis.

A case of late onset primary hyperoxaluria type I (PH-I) presented with black liver.

A 63-year-old woman who had received hemodialysis therapy since she fell acute on chronic renal failure 4 years ago presented with multiple joint pain. Nephrocalcinosis was not detected by abdominal X-ray when hemodialysis therapy was initiated. Laboratory testing showed azotemia, anemia, hypoproteinemia and mild liver dysfunction but no liver cirrhosis. Biopsied bone tissue demonstrated numerous calcium oxalate crystal depositions. Laparoscopy revealed black liver in macroscopic view. Histological studies showed numerous lipofuscin-like dark brown granules were deposited in hepatocytes. The activity of alanine : glyoxylate aminotransferase (AGT) was less than 0.1 U/g in biopsied patient's liver tissue. Generally, clinical symptoms demonstrated by Japanese primary hyperoxaluria type I (PH-I) patients are milder than those of European patients. Some PH-I patients may successfully avoid urinary tract calcification unless they fall into oliguria by some other causes. The lipofuscin granules are most likely the source of the dark color. Massive deposition of the lipofuscin granules indicated that the duration of the liver metabolic abnormality had lasted for long time. Thus, black liver may be related to a mild form of PH-I.

The schistosome granuloma: characterization of lymphocyte migration, activation, and cytokine production.

Granuloma formation and its regulation are dependent on lymphocytes. Therefore, we compared the characteristics of lymphocytes derived from the spleens and granulomas of Schistosoma mansoni-infected mice during the course of their disease. We examined lymphocyte cell cycle kinetics, migration, expression of activation Ags (CD69 and IL-2R), cytokine production (IL-2, IL-4, IFN-gamma), and apoptosis. Lymphocytes in the G2/M phase of the cell cycle and high levels of lymphocyte intracellular IL-2 were found in the spleen but not in the granuloma. Cell trafficking experiments showed Ag-specific recruitment of schistosomal egg Ag (SEA)-reactive lymphoblasts into granulomas in vivo, as well as recruitment to, residence within, and egress from granulomas in vitro. Granuloma-derived lymphocytes were more highly activated than splenic lymphocytes based on higher levels of CD69 and IL-2R expression. While the granuloma microenvironment was rich in Th2 cytokines, during peak granuloma formation, the lymphocytes per se from the spleen and granuloma did not exhibit a dominant Th1 or Th2 cytokine profile, producing low but similar levels of IL-4 and IFN-gamma. The discrepancy between high IL-2R expression and low levels of IL-2 protein production by granuloma lymphocytes was associated with increased apoptosis in the granuloma compared with the spleen. These findings support the hypothesis that granulomas may play a role in the regulation of systemic pathology in schistosomiasis by adversely affecting the survival of SEA-reactive, immunopathogenic T lymphocytes.

Analysis of T cell populations and IL-3 mRNA expression in mesenteric lymph node cells and intestinal intraepithelial lymphocytes in Strongyloides ratti-infected mice.

T cell populations and IL-3 mRNA expression were analysed in mesenteric lymph node cells and intestinal intraepithelial lymphocytes (IEL) in Strongyloides ratti-infected mice. On days 7 and 12 post-infection, 2.6 times as many mesenteric lymph node cells were present in S. ratti-infected mice compared with uninfected mice. Although the percentages of CD3+, CD4+ and CD8+ cells decreased during infection, the absolute numbers of these cell types increased on day 7 due to an overall increase in the mesenteric lymph node cell number. The CD4/CD8 ratio in IEL was increased on day 5, whereas no significant change in the CD4/CD8 ratio was observed in the mesenteric lymph node cells. Expression of IL-3 mRNA, which is an important cytokine for the induction of murine mucosal mastocytosis and S. ratti-expulsion, was examined in mesenteric lymph nodes and IEL of uninfected and infected mice. IL-3 mRNA was detected in mesenteric lymph nodes of S. ratti-infected mice but not detected in the lymph nodes of uninfected mice. IL-3 mRNA was detected in IEL from both infected and uninfected mice with an 20-fold increase in expression in IEL of infected mice. Overall, IL-3 mRNA levels were higher in IEL than in mesenteric lymph nodes following S. ratti-infection. Expression of IL-4, IL-10, stem cell factor (SCF or c-kit ligand) and IFN-gamma mRNA was also examined in these two tissues. IL-10 mRNA was not detected in any tissue examined and IFN-gamma mRNA levels were unaltered as a result of an S. ratti-infection. Elevated expression of mRNA for SCF (5-fold) and IL-4 (20-fold) was observed in the mesenteric lymph nodes of infected mice. In contrast, SCF mRNA levels were similar in IEL of uninfected and infected animals and only a modest increase in IL-4 mRNA was observed in IEL of infected mice.

The role of CD4+ and CD8+ T-cells in host morbidity and innate resistance to angiostrongylus cantonensis in the mouse.

Strain-dependent differences in host morbidity and mortality due to Angiostrongylus cantonensis infection have been established between C57BL/6 and BALB/c mice; C57BL/6 mice show rapid worm killing with low morbidity, whereas BALB/c mice indicate slow worm killing with high morbidity and mortality. To determine the possible roles of CD4+ and CD8+ T-cells in host morbidity and innate resistance to A. cantonensis infection we treated C57BL/6 and BALB/c mice with anti-CD4 or anti-CD8 monoclonal antibody and examined the changes in host morbidity and worm-killing activity. Our study indicates that anti-CD4 antibody treatment interferes with worm killing and improves the morbidity of A. cantonensis-infected BALB/c mice, whereas anti-CD8 antibody treatment fails to improve the morbidity. Tumor necrosis factor-alpha (TNF-alpha, or cachectin) production in infected mice was not correlated with host morbidity. Anti-IL-5 monoclonal antibody treatment also failed to affect the morbidity of infected BALB/c mice, although their worm-killing activity was restrained as shown in anti-CD4-treated mice. These findings clearly indicate that the morbidity of infected BALB/c mice is regulated by some unknown CD4+ T-cell-dependent mechanism but not by an IL-5-, eosinophil-, or TNF-alpha-dependent mechanism.

Mediastinal lymph node cells of Angiostrongylus cantonensis-infected rats respond to antigens and release interleukin-5 in vitro.

The kinetics of eosinophil growth and/or survival stimulating factor (Eo-stimulating factor) production in Angiostrongylus cantonensis-infected rats was assessed by in vitro marrow cultures. When lymphocytes, obtained from cervical, mediastinal or mesenteric lymph nodes of infected WKAH rats, were cultured with A. cantonensis antigens, Eo-stimulating factor activity was detected in the conditioned media obtained only from mediastinal lymph node cells at and after 35 days p.i. Eo-stimulating factor activity in the conditioned media was not detected before or at 20 days p.i. The kinetics of the factor was, therefore, almost identical to those of eosinophilia in bone marrow and peripheral blood. This Eo-stimulating factor activity was inhibited (maximum inhibition = 73%) by anti-mouse IL-5 monoclonal antibody in a dose-dependent fashion, indicating that the factor would be, at least in part, identical to IL-5. Similar Eo-stimulating factors were also detected in the conditioned media which were obtained by stimulating spleen cells from Wistar rats at 35-45 days p.i. with Con A. These data suggest that lymphocytes in the mediastinal lymph nodes, local lymph nodes near the adult worm habitat, could play an essential role in induction of eosinophilia in A. cantonensis-infected rats.

[Glucose intolerance after percutaneous ethanol injection therapy (PEI) in liver cirrhosis patients with hepatocellular carcinoma].

We studied the effect of percutaneous ethanol injection therapy (PEI) on glucose tolerance in liver cirrhosis patients with hepatocellular carcinoma. All of 10 patients underwent PEI and aspiration biopsy of the tumor on separate day. Two-time oral glucose tolerance tests (OGTT), before and after PEI, were performed in all patients. There were no significant changes in blood glucose and insulin chronologically measured on aspiration biopsy and PEI. To detect changes in glucose tolerance, we compared the results of OGTT before PEI with those of OGTT after PEI. On the basis of results of OGTT before PEI, patients were classified to impaired glucose tolerance group (4) and diabetes mellitus group (6). Blood glucose at 180 minutes on OGTT after PEI showed significantly higher value than that of OGTT before PEI, but insulin response was not suppressed. From these experiments we speculate that exaggerated insulin resistance due to injected ethanol may be one of the factors influencing glucose tolerance after PEI.